Genetic Variant SIRT1:c.*480T>C (chr10-67917073-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012238.5(SIRT1):c.*480T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 152,736 control chromosomes in the GnomAD database, including 532 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.030 ( 532 hom., cov: 32)

Exomes 𝑓: 0.043 ( 0 hom. )

Consequence

SIRT1
NM_012238.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

58 publications found

Variant links:

Genes affected

SIRT1 (HGNC:14929): (sirtuin 1) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

SIRT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012238.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT1	NM_012238.5	MANE Select	c.*480T>C	3_prime_UTR	Exon 9 of 9	NP_036370.2
SIRT1	NM_001142498.2		c.*480T>C	3_prime_UTR	Exon 8 of 8	NP_001135970.1
SIRT1	NM_001314049.2		c.*480T>C	3_prime_UTR	Exon 10 of 10	NP_001300978.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT1	ENST00000212015.11	TSL:1 MANE Select	c.*480T>C	3_prime_UTR	Exon 9 of 9	ENSP00000212015.6
SIRT1	ENST00000403579.1	TSL:1	c.*480T>C	3_prime_UTR	Exon 6 of 6	ENSP00000384063.1
SIRT1	ENST00000432464.5	TSL:5	c.*480T>C	3_prime_UTR	Exon 8 of 8	ENSP00000409208.1

Frequencies

GnomAD3 genomes

AF:

0.0302

AC:

4594

AN:

152158

Hom.:

529

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0689

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.415

Gnomad SAS

AF:

0.0973

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00295

Gnomad OTH

AF:

0.0244

GnomAD4 exome

AF:

0.0435

AC:

AN:

460

Hom.:

Cov.:

AF XY:

0.0331

AC XY:

AN XY:

272

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.0444

AC:

AN:

428

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0500

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0302

AC:

4602

AN:

152276

Hom.:

532

Cov.:

AF XY:

0.0367

AC XY:

2733

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00476

AC:

198

AN:

41566

American (AMR)

AF:

0.0697

AC:

1066

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.414

AC:

2142

AN:

5170

South Asian (SAS)

AF:

0.0974

AC:

470

AN:

4826

European-Finnish (FIN)

AF:

0.0404

AC:

429

AN:

10610

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00295

AC:

201

AN:

68026

Other (OTH)

AF:

0.0246

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

177

354

532

709

886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0148

Hom.:

489

Bravo

AF:

0.0347

Asia WGS

AF:

0.211

AC:

732

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.5

(source)

DANN

Benign

0.80

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over